Ten years ago, the food and drug administration first approved the use of plasminogen activators for thrombolytic therapy. It was originally recommended for the treatment of deep-vein thrombosis and serious pulmonary embolisms. This approach is now also used for treating acute peripheral arterial thrombosis and acute coronary thrombosis and for solubilizing clots in catheters and shunts.
With the development of recombinant DNA technology and the cloning and expression of tissue plasminogen activator (TPA), we have now entered a new age for thrombolytic agents with unique physiological properties and therapeutic promise. The original plasminogen activators that have been used clinically were streptokinase and urokinase. These agents produced in the patients a generalized lytic state which had a variety of side effects that were not directly targeted at solubilizing the fibrin clot. Tissue plasminogen activator, because of its fibrin binding capacity, enhances the selectivity of these agents for fibrin degradation. It is thus being greeted with great fanfare as the new generation of fibrinolytic agents.
Tissue plasminogen activator is not without its potential side effects, and, furthermore, its cost is prohibitive for use in many settings. For example, the V.A. in Gainesville will not authorize tissue plasminogen activator therapy over streptokinase therapy because of its enormous cost. Furthermore, the application of this fibrinolytic therapy to domestic animals or food production animals is limited by the enormous cost.
It is clear to most experts that the wonder drug nature of tissue plasminogen activator has been highly overrated. TPA has been found to have a very short half life in the body. Also, pharmacological doses of tissue plasminogen activator produce a significant bleeding risk for the patient, and in the case of coronary artery thrombosis, re-occlusion of the blood vessel following successful clot lysis occurs in a significant number of patients. The need for an inexpensive, and perhaps even better form of treatment is clearly evident. The use of combination therapies whereby existing compositions and methods are integrally linked in novel ways with new materials and procedures could enhance the effectiveness of plasminogen activators and possibly reduce the amount of plasminogen activator needed to achieve the desired results.
Recently, we have described in our laboratory the presence of a selective, high affinity receptor for human plasmin and other species of plasmin on the surface of certain group A streptococci (Lottenberg, R., C. C. Broder, M. D. P. Boyle [1987] Infect. Immun. 55:1914-1918). This receptor binds plasmin with a very high affinity and a very slow off-rate. Once bound, the enzyme retains its enzymatic activity and cannot be regulated by the natural physiological regulator of plasmin .alpha.2 antiplasmin. This means that bacteria with plasmin bound to their surfaces are potent, non-regulatable fibrinolytic agents.